NeoVax + CDX-301 + Nivolumab for Melanoma

Recruiting at1 trial location

Overseen by Patrick Ott, MD, PhD

Age: 18+

Sex: Any

Travel: May Be Covered

Time Reimbursement: Varies

Trial Phase: Phase 1

Recruiting

Sponsor: Dana-Farber Cancer Institute

Must not be taking: Immunosuppressants, Anti-cancer agents

Disqualifiers: Active brain metastases, Autoimmune disease, HIV, others

No Placebo Group

Breakthrough Therapy

Trial Summary

What is the purpose of this trial?

This trial is testing a personalized vaccine called NeoVax, combined with other drugs, to treat melanoma. The vaccine is made from the patient's own tumor proteins to help the immune system fight cancer. The study aims to find a safe way to use these treatments together and determine the right dose.

Will I have to stop taking my current medications?

The trial requires that you do not take any anti-cancer agents, investigational anti-cancer therapies, or immunosuppressive agents within six months of participating. If you are on such medications, you may need to stop them before joining the trial.

What data supports the effectiveness of this treatment for melanoma?

Research shows that vaccines targeting tumor neoantigens can improve the effectiveness of nivolumab, a drug used in this treatment, by increasing progression-free survival in patients with metastatic melanoma and other cancers. Personalized neoantigen vaccines have also been shown to provoke strong immune responses in melanoma patients, suggesting potential benefits for this treatment combination. ^{1 2 3 4 5}

Is the combination of NeoVax, CDX-301, and Nivolumab safe for humans?

Nivolumab, one of the components of the treatment, has been studied extensively and is generally considered safe, but it can cause immune-related side effects, which are reactions where the immune system attacks normal organs and tissues. These side effects can vary in severity, and ongoing research aims to identify which patients might experience more severe reactions. ^{6 7 8 9 10}

What makes the NeoVax + CDX-301 + Nivolumab treatment unique for melanoma?

This treatment is unique because it combines a personalized neoantigen vaccine (NeoVax) with CDX-301 and Nivolumab, aiming to enhance the immune system's ability to target melanoma cells specifically. The use of a personalized vaccine is designed to improve the effectiveness of Nivolumab, a drug that helps the immune system recognize and attack cancer cells, potentially leading to better outcomes than standard treatments. ^{1 2 6 11 12}

Research Team

Patrick Ott, MD, PhD

Principal Investigator

Dana-Farber Cancer Institute

Eligibility Criteria

Adults with stage IIIB/C/D or IV melanoma that's resectable or unresected, and not mucosal/uveal type. Must have good performance status, normal organ/marrow function, no severe allergies to study drugs, no HIV/AIDS or hepatitis B/C infection. Women must test negative for pregnancy and agree to contraception; men also need to use contraception.

Inclusion Criteria

Participant is willing and able to give written informed consent

I am not breastfeeding if I decide to participate in this study.

I agree to use contraception during and for 7 months after the study.

Exclusion Criteria

I have an autoimmune disease but it's either mild or under control.

You have been diagnosed with HIV or AIDS.

Any underlying medical condition, psychiatric condition or social situation that in the opinion of the investigator would compromise study administration as per protocol or compromise the assessment of AEs

Trial Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive NeoVax in combination with CDX-301 and either Nivolumab or Pembrolizumab. Nivolumab is administered every 4 weeks for up to 2 years, and Pembrolizumab is administered every 3 weeks for 3 doses followed by every 6 weeks for 15 doses.

Up to 2 years

Follow-up

Participants are monitored for safety and effectiveness after treatment

5 years

Treatment Details

Interventions

• CDX-301 (Immunostimulant)
• NEOVAX (Cancer Vaccine)
• Nivolumab (Checkpoint Inhibitor)

Trial Overview The trial is testing a combination of NeoVax (a personalized cancer vaccine), CDX-301, and Nivolumab against melanoma. Participants will receive these drugs to see if they work better together in treating the disease compared to current standard treatments.

Participant Groups

Group I: CDX-301 + Neovax + Pembrolizumab Experimental Treatment 3 Interventions

* Participants will have vaccine made from tissue collected from tumor biopsy, or from previously collected archival biopsy or surgical tissue. * Participants will receive neoadjuvant Pembrolizumab for 3 doses every 3 weeks, then undergo standard-of-care surgical resection. * Participants will receive adjuvant NeoVax and CDX-301. CDX-301 will be administered at a predetermined dose, dependent on the number of participants previously enrolled, for 5 days starting 2 days before the initiation of NeoVax. CDX-301 will then be administered at a predetermined dose dependent on the number of participants previously enrolled 2 days before and for 5 days coinciding with the administration of NeoVax on days 50 and 78. * Participants will receive adjuvant Pembrolizumab for 15 doses every 6 weeks.

Group II: CDX-301 + Neovax + Nivolumab Experimental Treatment 3 Interventions

* Participants will have vaccine made from tissue collected from metastatic tumor biopsy or surgical resection, or from previously collected archival biopsy or surgical tissue. * Participants will receive Nivolumab at a flat dose every 4 weeks up to two years. * Participants will receive CDX-301 at a predetermined dose dependent on the number of participants previously enrolled for 5 days starting 2 days before the initiation of NeoVax. CDX-301 will then be administered at a predetermined dose dependent on the number of participants previously enrolled 2 days before and for 5 days coinciding with the administration of NeoVax on days 50 and 78.

Who Is Running the Clinical Trial?

Dana-Farber Cancer Institute

Lead Sponsor

Trials

1,128

Recruited

382,000+

Dr. Benjamin L. Ebert

Dana-Farber Cancer Institute

Chief Executive Officer

MD from Harvard Medical School, PhD from Oxford University

Dr. Craig A. Bunnell

Dana-Farber Cancer Institute

Chief Medical Officer since 2012

MD from Harvard Medical School, MPH from Harvard School of Public Health, MBA from MIT Sloan School of Management

Celldex Therapeutics

Industry Sponsor

Trials

66

Recruited

5,900+

Anthony S. Marucci

Celldex Therapeutics

Chief Executive Officer since 2008

MBA from Columbia University, MHL from Brown University

Diane C. Young

Celldex Therapeutics

Chief Medical Officer since 2019

MD from Harvard Medical School, AB in Biochemical Sciences from Harvard University

Findings from Research

A vaccine targeting tumor neoantigens was tested in patients with metastatic melanoma, non-small cell lung cancer, and bladder cancer, showing improved progression-free survival compared to historical controls.

The vaccine effectively stimulated tumor-specific T cells, suggesting it may enhance the effectiveness of nivolumab, a common cancer immunotherapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Vaccine Increases PFS for Metastatic Tumors. [2020]

The phase 1b clinical trial showed that the combination of the personalized vaccine NEO-PV-01 with chemotherapy and the anti-PD-1 drug pembrolizumab was well tolerated in patients with first-line metastatic non-squamous NSCLC.

This treatment regimen successfully induced specific CD4+ T cell responses targeting neoantigens, suggesting a promising mechanism for enhancing the immune response against cancer.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Combining personalized neoantigen vaccination with chemotherapy and anti-PD-1 to treat NSCLC. Leung, CSK., Van den Eynde, BJ.[2022]

Personalized neoantigen-enhanced oncolytic adenoviruses, specifically MY-NEOVAX™, showed positive therapeutic effects in two heavily pretreated end-stage cancer patients, indicating potential for improved treatment outcomes.

Both patients experienced treatment benefits lasting over 12 months without significant toxicities or serious adverse events, along with documented stabilization of their tumors and improved overall health status.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Extended treatment with MY-NEOVAX, personalized neoantigen-enhanced oncolytic viruses, for two end-stage cancer patients. Bouvet, M., Reid, TR., Larson, C., et al.[2020]

In a proof-of-principle study involving three patients with advanced melanoma, personalized vaccines targeting unique tumor neoantigens successfully triggered strong and diverse T-cell responses.

The personalized vaccines were well tolerated by the patients, indicating a favorable safety profile for this innovative treatment approach.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Customizing vaccines for melanoma. [2015]

A personalized neoantigen nanovaccine combined with anti-PD-1 antibody treatment led to a significant clinical benefit in an advanced pancreatic cancer patient, resulting in an overall survival of 10.5 months after treatment.

The treatment successfully induced a robust T cell response against multiple vaccine peptides, indicating that this approach may effectively enhance immune responses in controlling progressive metastatic pancreatic cancer.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Advanced Pancreatic Cancer Patient Benefit From Personalized Neoantigen Nanovaccine Based Immunotherapy: A Case Report. Shao, J., Liu, Q., Shen, J., et al.[2023]

In a phase 3 trial involving 405 patients with advanced melanoma, nivolumab resulted in a significantly higher objective response rate (31.7%) compared to investigator's choice of chemotherapy (10.6%), indicating its superior efficacy as a treatment option.

Nivolumab was associated with fewer severe adverse effects compared to chemotherapy, with only 5% of patients experiencing serious drug-related side effects, suggesting it is a safer alternative for patients who have progressed after previous treatments.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Nivolumab versus chemotherapy in patients with advanced melanoma who progressed after anti-CTLA-4 treatment (CheckMate 037): a randomised, controlled, open-label, phase 3 trial. Weber, JS., D'Angelo, SP., Minor, D., et al.[2022]

In the phase III CheckMate 238 trial, 67.7% of patients receiving nivolumab experienced treatment-related adverse events (TRAEs), with the most common being pruritus and diarrhea, primarily occurring within the first 3 months of treatment.

Despite the high incidence of TRAEs, there was no significant association found between these adverse events and recurrence-free survival (RFS), indicating that the safety profile of nivolumab remains consistent and does not negatively impact long-term outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Adjuvant nivolumab for stage III/IV melanoma: evaluation of safety outcomes and association with recurrence-free survival. Mandala, M., Larkin, J., Ascierto, PA., et al.[2022]

In a phase 2 study of 23 patients with high-risk resectable melanoma, the combination of ipilimumab and nivolumab showed high response rates (73% overall response rate and 45% pathologic complete response) but also resulted in significant toxicity, with 73% of patients experiencing grade 3 treatment-related adverse events.

Nivolumab monotherapy had lower response rates (25% overall response rate and 25% pathologic complete response) but was associated with much lower toxicity (only 8% grade 3 treatment-related adverse events), suggesting that while combination therapy is effective, it comes with higher risks.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Neoadjuvant immune checkpoint blockade in high-risk resectable melanoma. Amaria, RN., Reddy, SM., Tawbi, HA., et al.[2021]

Nivolumab, an immune checkpoint inhibitor, shows strong antitumor activity but is associated with immune-related adverse events that can affect patient safety and treatment continuation, necessitating careful monitoring.

Long-term safety data, including a 5-year follow-up, suggests that nivolumab can be safely administered to various challenging patient subgroups, but identifying biomarkers for severe toxicity could improve patient selection for this therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

An update on the safety of nivolumab for the treatment of advanced melanoma. Czarnecka, AM., Rutkowski, P.[2021]

Nivolumab (OPDIVO) received accelerated FDA approval for treating unresectable or metastatic melanoma based on a 31.7% objective response rate in a study of 120 patients, showing promising efficacy after prior treatments.

The treatment demonstrated durable responses, with 87% of responding patients maintaining their response for at least 6 months, although it carries risks of immune-mediated adverse reactions that were monitored in a safety assessment of 268 patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

U.S. FDA Approval Summary: Nivolumab for Treatment of Unresectable or Metastatic Melanoma Following Progression on Ipilimumab. Hazarika, M., Chuk, MK., Theoret, MR., et al.[2023]

In cohort A, which included 30 patients with metastatic melanoma, the combination of an IDO/PD-L1 vaccine and nivolumab resulted in an impressive overall response rate of 80%, with 50% achieving a complete response and a median progression-free survival of 25.5 months.

Cohort B, where the vaccine was added to patients already on anti-PD-1 therapy, showed limited efficacy with only stable disease in 2 out of 10 patients and a median progression-free survival of just 2.4 months, indicating that the combination may not be effective for those with progressive disease during anti-PD-1 treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Long-term follow-up of anti-PD-1 naïve patients with metastatic melanoma treated with IDO/PD-L1 targeting peptide vaccine and nivolumab. Lorentzen, CL., Kjeldsen, JW., Ehrnrooth, E., et al.[2023]

The KEYNOTE-D36 trial is a phase II study designed to evaluate the safety and effectiveness of the personalized neoepitope vaccine EVX-01 combined with pembrolizumab in patients with unresectable or metastatic melanoma who have not previously received checkpoint inhibitor therapy.

The primary goal of the trial is to determine if EVX-01 can enhance the overall response rate in patients who initially show stable disease or a partial response to pembrolizumab, providing critical data before advancing to larger phase III trials.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

KEYNOTE - D36: personalized immunotherapy with a neoepitope vaccine, EVX-01 and pembrolizumab in advanced melanoma. Long, GV., Ferrucci, PF., Khattak, A., et al.[2022]

References

1. United States pubmed.ncbi.nlm.nih.gov

Vaccine Increases PFS for Metastatic Tumors. [2020]

2. United States pubmed.ncbi.nlm.nih.gov

Combining personalized neoantigen vaccination with chemotherapy and anti-PD-1 to treat NSCLC. [2022]

3. England pubmed.ncbi.nlm.nih.gov

Extended treatment with MY-NEOVAX, personalized neoantigen-enhanced oncolytic viruses, for two end-stage cancer patients. [2020]

4. United States pubmed.ncbi.nlm.nih.gov

Customizing vaccines for melanoma. [2015]

5. Switzerland pubmed.ncbi.nlm.nih.gov

Advanced Pancreatic Cancer Patient Benefit From Personalized Neoantigen Nanovaccine Based Immunotherapy: A Case Report. [2023]

6. England pubmed.ncbi.nlm.nih.gov

Nivolumab versus chemotherapy in patients with advanced melanoma who progressed after anti-CTLA-4 treatment (CheckMate 037): a randomised, controlled, open-label, phase 3 trial. [2022]

7. England pubmed.ncbi.nlm.nih.gov

Adjuvant nivolumab for stage III/IV melanoma: evaluation of safety outcomes and association with recurrence-free survival. [2022]

8. United States pubmed.ncbi.nlm.nih.gov

Neoadjuvant immune checkpoint blockade in high-risk resectable melanoma. [2021]

9. England pubmed.ncbi.nlm.nih.gov

An update on the safety of nivolumab for the treatment of advanced melanoma. [2021]

10. United States pubmed.ncbi.nlm.nih.gov

U.S. FDA Approval Summary: Nivolumab for Treatment of Unresectable or Metastatic Melanoma Following Progression on Ipilimumab. [2023]

11. England pubmed.ncbi.nlm.nih.gov

Long-term follow-up of anti-PD-1 naïve patients with metastatic melanoma treated with IDO/PD-L1 targeting peptide vaccine and nivolumab. [2023]

12. England pubmed.ncbi.nlm.nih.gov

KEYNOTE - D36: personalized immunotherapy with a neoepitope vaccine, EVX-01 and pembrolizumab in advanced melanoma. [2022]